The goal of this study is to define the structural requirements, especially sterochemical aspects, for optimum interaction of agonists and antagonists at receptor sites of dopaminergic neurons in different regions of mammalian brain, and to isolate and characterize such receptors using photo-affinity labeling techniques. The results of this study bear on the biochemical etiology of schizophrenia, believed to relate to abnormalities in dopaminergic neurotransmission, and to the mechanism(s) of action of neuroleptic (antipsychotic) drugs, which inhibit such neurotransmission principally by blockade of postsynaptic receptors. We intend to determine the heterogeneity of agonist and antagonist receptors as measured by the specific binding affinity of various classes of neuroleptics to receptors using a variety of radiolabeled neuroleptics, and the specificity of receptor activity of stereoisomeric agonists and antagonists in tissues isolated from different dopaminergic neuronal systems in rat and calf brain. Such studies could lead to the rational design of neuroleptics and antiParkinsonian drugs which possess minimal neurological side effects. Syntheses are outlined of rigid analogs of dopamine in which the geometry of the dopamine moiety is either fixed or limited conformationally, so that the pattern of in vitro receptor activity (binding and adenylate cyclase assays) can be directly correlated with dopamine geometry. Similar studies are planned on cyclized chlorpromazine derivatives and analogs of butaclamol. Finally, syntheses are outlined of agonist and neuroleptic analogs which should bind to specific receptors, and which contain functional groups which can be made to bind covalently to the receptor(s) upon ultraviolet excitation of the receptor-substrate complex. The detailed protocol specifies procedures for isolating and characterizing bound catecholamine and neuroleptic receptors fragments using radiochemical methods. This represents the first attempt to use photoaffinity labeling techniques in the characterization of catecholamine and neuroleptic receptors on the molecular level.